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    Clinical Trial Results:
    A randomised controlled trial to compare the safety and effectiveness of doxycycline (200 mg/day) with prednisolone (0.5 mg/kg/day) for initial treatment of bullous pemphigoid

    Summary
    EudraCT number
    		 2007-006658-24
    Trial protocol
    		 GB   DE  
    Global end of trial date
    31 Oct 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Mar 2019
    First version publication date
    10 Mar 2019
    Other versions
    Summary report(s)
    		 A randomised controlled trial to compare the safety, effectiveness and cost-effectiveness of doxycycline (200 mg/day) with that of oral prednisolone (0.5 mg/kg/day) for initial treatment of bullous pe

    Trial information

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    Trial identification
    Sponsor protocol code
    08024
    Additional study identifiers
    ISRCTN number
    		 ISRCTN13704604
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Nottingham
    Sponsor organisation address
    Research and Innovation, Jubilee Conference Centre, Triumph Road, Nottingham, United Kingdom, NG8 1DH
    Public contact
    Professor Hywel Williams, University of Nottingham , +44 1158231048, hywel.williams@nottingham.ac.uk
    Scientific contact
    Ms Angela Shone, University of Nottingham , +44 1158467906, sponsor@nottingham.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Oct 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To evaluate the effectiveness, safety and cost-effectiveness of a strategy of initiating BP treatment with oral doxycycline or oral prednisolone. We hypothesised that starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral prednisolone.
    Protection of trial subjects
    Trial oversight was by a Trial Steering Committee and an independent Data Monitoring Committee. Ethics permission was granted for all participating sites.
    Background therapy
    		 To reflect clinical practice additional application of potent topical corticosteroids (up to 30 g/week, preferably mometasone furoate) to affected areas (or if in the doxycycline arm a switch to oral corticosteroids if symptoms and blister control were inadequate) was permitted except between weeks 3 and 6. Moisturiser applied to blisters and erosions at any time was permitted.
    Evidence for comparator
    		 Oral prednisolone is thought to be effective at reducing the blisters in BP, but it has many side effects as indicated in previous trials comparing topical corticosteroids with oral corticosteroids (1-3). Doxycycline is perceived to be less effective but probably has fewer side effects. (1) Joly P, Roujeau JC, Benichou J, Picard C, Dreno B, Delaporte E, et al. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med 2002;346:321–7.http://dx.doi.org/10.1056/NEJMoa011592 (2) Joly P, Roujeau JC, Benichou J, Delaporte E, D’Incan M, Dreno B, et al. A comparison of two regimens of topical corticosteroids in the treatment of patients with bullous pemphigoid: a multicenter randomized study. J Invest Dermatol 2009;129:1681–7. http://dx.doi.org/10.1038/ jid.2008.412 (3) Fuertes de Vega I, Iranzo-Fernandez P, Mascaro-Galy JM. Bullous pemphigoid: clinical practiceguidelines. Actas Dermosifiliogr 2014;105:328–46. http://dx.doi.org/10.1016/j.ad.2012.10.022
    Actual start date of recruitment
    02 Mar 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 241
    Country: Number of subjects enrolled
    Germany: 12
    Worldwide total number of subjects
    253
    EEA total number of subjects
    253
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    22
    From 65 to 84 years
    167
    85 years and over
    64

    Subject disposition

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    Recruitment
    Recruitment details
    		 UK - 1st March 2009 - 31st October 2013 Germany - 1st February 2010 - 31st October 2013

    Pre-assignment
    Screening details
    		 Inclusion Adults capable of consent Clinical diagnosis of BP Min 3 significant blisters in past week (at least 2 body sites) Positive direct or indirect immunofluorescence No blisters/treatment for BP in past year Exclusion Systemic medication for current BP Oral prednisolone/doxycycline past 12 weeks Mostly/entirely mucosal pemphigoid

    Period 1
    Period 1 title
    Weeks 0 to 6
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst
    Blinding implementation details
    Investigator and analyst blinded to the treatment allocation for this period

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention: doxycycline
    Arm description
    		 200 mg/day of doxycycline taken as a single, daily dose (brand not specified).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doxycycline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg/day of doxycycline taken as a single, daily dose (brand not specified).

    Arm title
    		 Comparator: prednisolone
    Arm description
    		 0.5 mg/kg/day of prednisolone taken as a single, daily dose (brand not specified).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg/kg/day of prednisolone taken as a single, daily dose (brand not specified).

    Number of subjects in period 1
    		Intervention: doxycycline Comparator: prednisolone
    Started
    132
    121
    Completed
    112
    101
    Not completed
    20
    20
         Consent withdrawn by subject
    16
    10
         Died prior to visit
    2
    5
         Missed assessment
    2
    5
    Period 2
    Period 2 title
    Weeks 7 to 52
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention: doxycycline
    Arm description
    		 200 mg/day of doxycycline taken as a single, daily dose (brand not specified).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doxycycline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg/day of doxycycline taken as a single, daily dose (brand not specified).

    Arm title
    		 Comparison: prednisolone
    Arm description
    		 0.5 mg/kg/day of prednisolone taken as a single, daily dose (brand not specified).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg/kg/day of prednisolone taken as a single, daily dose (brand not specified).

    Number of subjects in period 2
    		Intervention: doxycycline Comparison: prednisolone
    Started
    112
    101
    Completed
    78
    78
    Not completed
    36
    28
         Consent withdrawn by subject
    20
    13
         Died prior to visit
    12
    14
         Lost to follow-up
    4
    1
    Joined
    2
    5
         Missed visit period 1
    2
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention: doxycycline
    Reporting group description
    		 200 mg/day of doxycycline taken as a single, daily dose (brand not specified).

    Reporting group title
    Comparator: prednisolone
    Reporting group description
    		 0.5 mg/kg/day of prednisolone taken as a single, daily dose (brand not specified).

    Reporting group values
    		 Intervention: doxycycline Comparator: prednisolone Total
    Number of subjects
    		 132 121 253
    Age categorical
    Age at entry to period 1
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 8 14 22
        From 65-84 years
    		 89 78 167
        85 years and over
    		 35 29 64
    Gender categorical
    Units: Subjects
        Female
    		 63 57 120
        Male
    		 69 64 133
    Subject analysis sets

    Subject analysis set title
    Period 1 Difference pred-doxy week 6 success
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Non-inferiority comparison, week 6. Treatment success defined as 3 or fewer blisters at week 6 regardless of treatment modification. Percentage difference between prednislone and doxycylcine

    Subject analysis set title
    Primary Safety outcome: proportion difference
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Superiority comparison. The proportion of participants with grade 3 (severe), 4 (life-threatening) and 5 (death) adverse events that were possibly, probably or definitely related to the treatment in the 52 weeks following randomisation, comparison prednisolone - doxycycline.

    Subject analysis sets values
    		 Period 1 Difference pred-doxy week 6 success Primary Safety outcome: proportion difference
    Number of subjects
    169
    234
    Age categorical
    Age at entry to period 1
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units:
        
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Intervention: doxycycline
    Reporting group description
    		 200 mg/day of doxycycline taken as a single, daily dose (brand not specified).

    Reporting group title
    Comparator: prednisolone
    Reporting group description
    		 0.5 mg/kg/day of prednisolone taken as a single, daily dose (brand not specified).
    Reporting group title
    Intervention: doxycycline
    Reporting group description
    		 200 mg/day of doxycycline taken as a single, daily dose (brand not specified).

    Reporting group title
    Comparison: prednisolone
    Reporting group description
    		 0.5 mg/kg/day of prednisolone taken as a single, daily dose (brand not specified).

    Subject analysis set title
    Period 1 Difference pred-doxy week 6 success
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Non-inferiority comparison, week 6. Treatment success defined as 3 or fewer blisters at week 6 regardless of treatment modification. Percentage difference between prednislone and doxycylcine

    Subject analysis set title
    Primary Safety outcome: proportion difference
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Superiority comparison. The proportion of participants with grade 3 (severe), 4 (life-threatening) and 5 (death) adverse events that were possibly, probably or definitely related to the treatment in the 52 weeks following randomisation, comparison prednisolone - doxycycline.

    Primary: Primary endpoint: Three or less blisters at 6 weeks

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    End point title
    		 Primary endpoint: Three or less blisters at 6 weeks
    End point description
    Proportion of participants who achieved treatment success (three or less blisters) at 6 weeks
    End point type
    Primary
    End point timeframe
    Treatment success at 6 weeks
    End point values
    		 Intervention: doxycycline Comparator: prednisolone
    Number of subjects analysed
    112
    101
    Units: Percentage
    78
    91
    Statistical analysis title
    		 Difference in proportions: prednis - doxycycli
    Comparison groups
    Intervention: doxycycline v Comparator: prednisolone
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    18.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 9.8
         upper limit
    		 27.6
    Variability estimate
    Standard error of the mean

    Primary: Primary endpoint: proportion of grade 3 or above AEs 52 weeks

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    End point title
    		 Primary endpoint: proportion of grade 3 or above AEs 52 weeks
    End point description
    Grade 3, 4 and 5 side effects (treatment-related severe, life-threatening or fatal (as per CTC criteria) v3.0 by 52 weeks
    End point type
    Primary
    End point timeframe
    52 weeks
    End point values
    		 Intervention: doxycycline Comparison: prednisolone Primary Safety outcome: proportion difference
    Number of subjects analysed
    112
    101
    234
    Units: Percentage
    112
    101
    234
    Statistical analysis title
    		 Primary o/c: period 2, week 52, superiorty compar
    Comparison groups
    Intervention: doxycycline v Comparison: prednisolone v Primary Safety outcome: proportion difference
    Number of subjects included in analysis
    447
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    18.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6
         upper limit
    		 30.85

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    0-52
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    1
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Individual adverse vents were not reported. Grade categorisation of all adverse events were collected and analysed as part of the primary safety outcome. Details in the attached summary paper.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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